Despite recent progress in diagnosis and treatment of non-small cell lung cancer (NSCLC), survival continues to be poor. Better understanding of the molecular mechanisms that lead to lung cancer and other malignancies are urgently necessary. Most of the research over the last decade in lung cancer has focused on oncogenes, as highlighted in Projects 3, 4, and 5 of this SPORE submission. However research regarding tumor suppressor genes involved in lung cancer has lagged behind, and no specific therapies targeting these genes have emerged to help patients. Since the original Lung Cancer SPORE proposal in 2002, we have studied two specific genes necessary for normal lung development that may act as tumor suppressor genes in lung cancer. These are the transcription factors C/EBPalpha and Foxa2. Our groups'work has demonstrated that both factors act in a pathway commonly downregulated in many lung cancers and further experiments will enhance understanding of their clinical consequences. The goal of this research is to eventually devise therapies that can re-establish their differentiation-inducing and tumor suppressive pathways, which may expand the therapeutic and chemopreventive options for this malignancy. Therefore, based on the novel findings obtained in 2003 to 2007, we propose to further expand our studies of these transcription factors and move the pathways and potential targets closer to effective clinical applications in malignancies of the airway epithelium with the following Specific Aims: 1) To establish the main mechanisms of inactivation of Foxa2 in lung cancer, its downstream targets (15-PGDH) and prognostic significance;2} To establish the induction of C/EBPbeta as a novel strategy for lung cancer treatment;3) To evaluate the synthetic triterpenoids (CDDO and derivatives) as compounds capable of inducing C/EBPbeta and as potent therapeutic options for lung cancer. The foreseeable clinical potential of these studies are the identification of novel prognostic markers in early stage non-small cell lung cancer (Foxa2) and the sound introduction of oral compounds - currently in human phase I clinical trials (as is the case of CDDO-Me) - that can re-activate the crucial C/EBP lung differentiation pathway and halt proliferation as well as induce apoptosis in NSCLC. These studies will likely be the springboard to future clinical trials in patients with this malignancy.